Initial presentation of early rheumatoid arthritis

Objectives To study the joint distribution and clinical picture of rheumatoid arthritis (RA) at the initial presentation in seropositive (anti-citrullinated protein antibody (ACPA) and/or rheumatoid factor (RF) positive) and negative patients and the effect of duration of symptoms on the clinical picture. Methods Data of patients who received reimbursement for DMARDs for newly diagnosed RA in 1/2019 to 9/2021 were extracted from the national databases. Joint counts, presence of symmetrical swelling, other disease activity measures, and patient reported outcomes (PROs) were compared in seropositive and negative patients. Regression analyses were applied to compare clinical variables in patients with duration of symptoms of <3, 3–6, and >6 months, adjusted for age, sex, and seropositivity. Results Data of 1816 ACPA and RF-tested patients were included. Symmetrical swelling was present in 75% of patients. Seronegative versus positive patients had higher value for all disease activity measures and PROs including median swollen joint count (SJC46 10 versus 5) and DAS28 (4.7 versus 3.7), (p<0.001). Patients diagnosed in <3 months had higher median pain VAS (62 versus 52 and 50, p<0.001) and HAQ (1.1 versus 0.9 and 0.75, p = 0.002) compared to those with a duration of symptoms of 3–6 and >6 months. Patients diagnosed >6 months were ACPA-positive more frequently (77% versus 70% in other groups, p = 0.045). Conclusion Incident RA presents mainly as symmetric arthritis. Seronegative patients have higher disease burden at the initial presentation. Patients experiencing more severe pain and decreased functional ability are diagnosed earlier, regardless of ACPA- status.

We have now made all the corrections you suggested to us for the manuscript called ''initial presentation of rheumatoid arthritis''. I hope this is now acceptable for your paper.  This study was conducted as a register-based study using data from the Finnish Rheumatology Quality Register, which is kept by the Finnish Institute for Health and Welfare (THL) and granted approval for the study. In a register-based study, patient consent was not required.

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The data underlying the results presented in the study are available from (include the name of the third party and contact information or URL). This text is appropriate if the data are owned by a third party and authors do not have permission to share the data. In the 2010 ACR/EULAR classification criteria for RA, more emphasis has been placed on serology (5) without requirement for symmetry. With the 2010 criteria, early RA is now presented mainly in two forms with 6 criteria fulfilled, either seropositive RA, which can be oligoarthritis without elevated inflammatory markers, or seronegative RA, which is usually polyarthritis with elevated inflammatory markers. In fact, it is getting obvious that autoantibodies are the hallmark of RA and seronegative RA is a distinct entity (6) with different risk factors (7,8) and outcomes compared to seropositive RA (9). Our recent study indicated that seronegative RA turns out to be a spectrum of different conditions when observed for 10 years (10,11). Nonetheless, seronegative active arthritis requires early identification and tightly controlled treatment with Disease Modifying Antirheumatic Drugs (DMARDs) as it also causes significant treatable disease burden to patients (12).
First in the 1970's (13) and more widely since the 1990's, it has been recognized that RA should be identified and its treatment initiated as soon as possible to facilitate good outcomes (13,14). With multiple studies showing that early recognition is crucial, it has since been emphasized as an important approach for the management of RA (15). It has also been shown that treatment initiation within the first 12 weeks after the first symptoms might be the best window of opportunity in terms of treatment outcomes (16,17). Some studies suggest that the duration of symptoms has decreased during the current millennium (18). However, there are still notable delays in terms of treatment initiation. For example, only 31 % of patients with incident RA were examined by a rheumatologist 5 within 12 weeks of the first symptoms in the Netherlands in 1993-2006 (19). In the UK, patients with early RA visit their general practitioner 4 times on average before being referred to a specialist according to a report from 2008-2009 (20). Therefore, our objective was to study the initial presentation of RA in a nationwide setting, with a focus on the serological status and symmetry of joint swelling, as well as the effect of duration of symptoms.

Methods
Setting. Patients with incident RA are diagnosed and treated in rheumatology outpatient clinics in Finland. According to the national guidelines, DMARDs are started at the time of the diagnosis together with a medication reimbursement application, prepared by the rheumatologist. The reimbursement is granted by the Social Insurance Institution of Finland (KELA) for DMARDs. In addition to granting reimbursements for patients with chronic illnesses, such as RA, KELA also maintains a database of the individuals, containing the ICD code of the diagnosis, date of the reimbursement and basic demographic data of the individuals.
For the current study, patients who received their first reimbursement for DMARDs prescribed for the treatment of RA between 1/2019-9/2021 were identified in the KELA database. Clinical and demographic data were extracted from The Finnish Rheumatology Quality Register, using the individual identification code. To capture the data at the time of the diagnosis, clinical data were extracted from the most recent visit within 0 to 90 days prior to the date of the medication reimbursement; visits occurred between 23 rd November 2018 and 30 th August 2021. All patients were over 16 years old and could not be diagnosed as any other specific arthritis. The ACR/EULAR 2010 classification criteria were used to aid in diagnosing the patients (5).
Variables. Following variables were collected at the time of the diagnosis of RA and were available for analyses.  Duration of symptoms is the time between the first symptoms and the diagnosis of RA, recorded in months. At the initial visit, the patient was asked when he/she recognized the first symptoms of RA.
ACPA-positivity was defined by the laboratory reference values, which was ≥ 7 kU/l. RF-positivity was defined by the laboratory reference values, being ≥ 15 IU/ml. Fulfilment of the ACR/EULAR 2010 criteria was calculated by the examining physician, who counts the items in the ACR/EULAR 2010-criteria. If the total score adds up to 6 or more points, the ACR/EULAR 2010-criteria are met, when other reasons that can explain the condition are excluded (5).
Joint counts. The presence of swollen and tender joints was calculated using a 46 joint count including proximal interphalangeal (PIP), and metacarpophalangeal (MCP) joints, interphalangeal (IP) joints of the thumbs, wrists, metatarsophalangeal (MTP) joints, distal interphalangeal (DIP) joints of big toes, temporomandibular joints as well as ankle-, knee-, hip-, elbow-and shoulder joints.
Symmetrical swelling was analyzed from the MCPs, PIPs, wrists, MTPs, knees, ankles and the elbows, according to the 1987 criteria (1). A patient was considered to have symmetrical swelling if he/she had bilateral swelling in the same anatomical site. Symmetrical joint tenderness wasn't analyzed as it wasn't in the 1987 criteria (1).
CRP and ESR were determined according to the laboratory reference values for women and men in different age groups. A reference value of below 10 mg/l was normal for CRP. An elevated ESR included values of ≥ 20 mm/h for women younger than 50 years, ≥ 30 mm/h for women over 50 years and ≥42 mm/h for women over 85 years and ≥ 15 mm/h for men younger than 50 years, ≥20 mm/h for men over 50 years and ≥30 mm/h for men over 85 years.
DAS28 was used to describe disease activity (21).
Dr.global included the physicians' assessment of rheumatic activity on the 0-100 mm Visual Analog Scale (VAS), where 0 equals no disease activity and 100 maximal disease activity.
PROs included the self-assessment of pain, fatigue, and PGA on the 0-100 mm VAS, where 0 equals no symptoms and 100 maximal discomfort.
HAQ was used to describe the functional capacity of patients. It is scored from 0 to 3, a score of <0.5 is a sign of good functional status. In this study, we used HAQ without ''aids and devices'' due to its better accuracy in clinical studies (22,23).
The Initial Medications were analyzed in following groups:

Ethical issues.
This study was conducted as a register-based study using data from the Finnish Rheumatology Quality Register, which is kept by the Finnish Institute for Health and Welfare (THL), which granted the approval for the study. In a register-based study, patient consent was not required.

Demographic variables
A total of 2017 patients with incident RA were identified in the database. ACPA and/or RF were available for 1816 (90 %) patients, which were included in the analyses. Of these, 1444 (80 %) were seropositive and 372 (20 %) were seronegative. A total of 5 (0.3 %) seropositive patients weren't tested for ACPA, as they were already RF-positive. Vice-versa, 83 (6 %) patients weren't tested for RF, as they already had a positive ACPA-result. The mean (SD) age was 59 (16) years for all patients.
A total of 19 % of all patients were current smokers and 55 % had ever smoked. The corresponding proportions were 21 % and 57 % for seropositive patients and 12 % and 46 % for seronegative patients (p<0.001 for both comparisons, adjusted for age and sex). In terms of employment status, a total of 69 % of all patients were employed, 20 % disabled, 8 % unemployed and 4 % weren't currently in work force. No major differences were found between seropositive and negative patients. (Table 1). 10 The median (IQR) duration of symptoms before being diagnosed was 4 (2, 10) for all patients. For seropositive patients it was 5 (2, 10) and 4 (2,8)

Pattern and symmetry of joint involvement at the initial presentation
At the initial presentation, wrists were the most commonly affected joints, with 43.5 % of patients having a swollen left wrist and 43.6 % a swollen right wrist. Any joint from the right MCP's was swollen in 9.5 to 34.9 % of patients and in 9. . The corresponding proportions were 9.6 % and 7.9 % for shoulders, 13.5 % and 12.8 % for ankles, 6.8 % and 5.9 % for elbows and 1.9 % and 2.2 % for the hips (S1 Table).
At the initial presentation of RA, a total of 75 % of all patients had symmetrical swelling in any of the anatomical sites.  Fig 1).

Figure 1. Proportions of patients with symmetrical swelling by anatomical site in seropositive and
seronegative patients, at the initial presentation of RA.

Initial medication
A total of 17 % of seropositive patients and 23 % of seronegative patients started with MTX monotherapy, 72% and 67% started MTX + csDMARD, 10% and 11% started csDMARD(s) only, while bDMARDs and JAK-inhibitors were started only for a few patients. GCs were started for 82 % of seropositive and 94 % of seronegative patients (Table 2).  fatigue and PGA, the differences between groups were minor and mostly statistically not significant (S2 Table).
Clinical variables between ACPA-positive but RF-negative and RF-positive but ACPA-negative patients   Table 3. Clinical data of patients that were only ACPA-or RF-positive.

Discussion
Our main observation was that early RA is still mainly presented as symmetric arthritis, as three out of four patients had symmetrical swelling in any of the anatomical sites of the 1987 criteria at the initial presentation (1). Overall, the wrists were the most commonly swollen joints by a significant margin (S1 Table). Symmetrical swelling was detected more often overall and at all sites in ACPA negative patients. This was an expected finding since more swollen joints are required to fulfill the criteria for seronegative RA (5). Seronegative patients had also higher SJC46 at the initial presentation (median 5 versus 10). Interestingly, the presence of symmetrical swelling was only slightly higher for seronegative patients in the MTPs (34 % versus 39 %, p=0.097) ( Clinical measures and medication. In terms of clinical data, seronegative RA presented significantly higher activity by almost all variables used in the study (Table 2). Similar differences were found between solely ACPA-positive and solely RF-positive patients, though most of the findings weren't statistically significant (Table 3). In ESR, the difference was only minor between seropositive and seronegative patients (20 versus 24, p=0.172) ( Table 2). Seropositive patients were more likely to fulfill the ACR/EULAR 2010 criteria (82 % versus 78) at the time of diagnosis. Patients with seropositive RA were also current smokers more often, (21 % versus 12 % current smokers) ( Table   1), as smoking is a known risk-factor for ACPA-positive RA (24). In terms of medication, GCs and MTX as monotherapy was used more frequently in patients that were diagnosed with seronegative RA.
The more prevalent use of GCs indicates that some of the diagnoses might have been actually polymyalgia rheumaticas, as our previous studies have suggested (10,11).
Comparison to other studies.  (26). This is in line with our results, where the median duration of symptoms was five months for seropositive and four months for seronegative RA ( Table 1).
The effect of duration of symptoms on the initial presentation. The overall median SJC46 was the same in all groups by duration of symptoms (median 6 joints) (S2 Table) and median DAS28 was higher in the group of patients with a delay of < 3 months compared to patients with a delay of >6 months (4.1 versus 3.8, p=0.016, adjusted for age and sex). Interestingly, patients with a delay of <3 and 3-6 months were also older than in the group with a delay of >6 months (mean age of 61 and 58 in groups with a delay of <3 and 3-6 months and 56 in the group with a delay of >6 months, p<0.001) (S2 Table). It has been shown that older patients utilize health care services more frequently, which might explain the finding (27).  Table), which indicates that patients experiencing more severe symptoms and limitations in physical activity might seek health care services earlier. ACPA-positivity isn't necessarily associated with the severity of symptoms. A previous Polish study has shown that the second most important factor for the duration of symptoms of RA is patients' conviction that the condition will resolve on its own (28).

Strengths and limitations
The main strength of this study was its large patient population from almost all health care regions, in Finland and that patient data was documented recently allowing an accurate presentation of the current clinical picture.
Weaknesses. Although all health care regions are included in the quality register, at the time that was defined as the focus period, not all regions actively recorded clinical data. Therefore, probably not all patients with incident RA could be included. Furthermore, although not recommended, patients may still be diagnosed along with receiving treatment initiation in private practice, which are not involved in the quality register, yet.
One of the weaknesses in register studies is missing data, although the completeness was as high as ≥95% for joint counts and ≥78 % for PROs.

Conclusions
Our results indicate that the initial presentation of early RA is still mostly symmetric seropositive arthritis. Furthermore, we found that seronegative RA has significantly higher inflammatory activity and disease burden at the initial presentation by several clinical variables, compared to seropositive cases. However, 25 % of patients in the current study didn't have symmetrical swelling at the initial presentation, which is why all patients with clinical joint inflammation of unknown reason ought to be tested for ACPA and RF and referred to a rheumatology unit if ACPA and/or RF ispositive. Our observations are encouraging in terms that patients experiencing more severe pain and decrease in functional ability might seek health care services earlier. We also found that ACPA--positivity is not necessarily associated with the severity of symptoms.  In the 2010 ACR/EULAR classification criteria for RA, more emphasis has been placed on serology (5) without requirement for symmetry. With the 2010 criteria, early RA is now presented mainly in two forms with 6 criteria fulfilled, either seropositive RA, which can be oligoarthritis without elevated inflammatory markers, or seronegative RA, which is usually polyarthritis with elevated inflammatory markers. In fact, it is getting obvious that autoantibodies are the hallmark of RA and seronegative RA is a distinct entity (6) with different risk factors (7,8) and outcomes compared to seropositive RA (9). Our recent study indicated that seronegative RA turns out to be a spectrum of different conditions when observed for 10 years (10,11). Nonetheless, seronegative active arthritis requires early identification and tightly controlled treatment with Disease Modifying Antirheumatic Drugs (DMARDs) as it also causes significant treatable disease burden to patients (12).
First in the 1970's (13) and more widely since the 1990's, it has been recognized that RA should be identified and its treatment initiated as soon as possible to facilitate good outcomes (13,14). With multiple studies showing that early recognition is crucial, it has since been emphasized as an important approach for the management of RA (15). It has also been shown that treatment initiation within the first 12 weeks after the first symptoms might be the best window of opportunity in terms of treatment outcomes (16,17). Some studies suggest that the duration of symptomsiagnostic delay has decreased during the current millennium (18). However, there are still notable delays in terms of treatment initiation. For example, only 31 % of patients with incident RA were examined by a Cases. The focus of this study is ACPA-status, instead of seropositivity, which also includes rheumatoid factor (RF) positive, but ACPA-negative patients. The reason for this was that RF has been shown to be elevated in many other connective tissue disorders, bacterial and viral infections, malignancies and liver diseases (22), it is a less specific marker for RA (23) and ACPA-positivity is a stronger predictor of a more severe disease course and erosive disease (24). Duration of symptoms, which is the time between the first symptoms and the diagnosis of RA , recorded in months. At the initial visit, the patient was asked when he/she recognized the first symptoms of RA. from the patient and it was recorded in months.
ACPA-positivity was defined by the laboratory reference values, which was ≥ 7 kU/l. In this study, RF-positivity wasn't included in the analyses. DAS28 was used to describe disease activity (21). PROs included the self-assessment of pain, fatigue, and PGA on the 0-100 mm VAS, where 0 equals no symptoms and 100 maximal discomfort.

RF-positivity
HAQ was used to describe the functional capacity of patients. It is scored from 0 to 3, a score of <0.5 is a sign of good functional status. In this study, we used HAQ without ''aids and devices'' due to its better accuracy in clinical studies. (22,23) The Initial Medications were analyzed in following groups:

Ethical issues.
This study was conducted as a register-based study using data from the Finnish Rheumatology Quality Register, which is kept by the Finnish Institute for Health and Welfare (THL) and, which granted the approval for the study. In a register-based study, patient consent was not required.  (16) (p<0.001), 60 (14) and 57 (16). For ACPA negative patients, the same numbers were 61 (16), 63 (14) and 59 (16) (Table 1).

Formatted
A total of 19 % of all patients were current smokers and 55 % had ever smoked. The corresponding proportions were 21 % and 578 % for seroACPA positive patients and 12 % and 46 % for seroACPAnegative negative patients (p<0.001 for both comparisons, adjusted for age and sex). In terms of employment status, a total of 69 % of all patients were employed, 20 % disabled, 87 % unemployed and 4 % weren't currently in work force. No major differences were found between seroACPA positive and negative patients. (Table 1).
The proportions of patients fulfilling the ACR/EULAR 2010-criteria at the initial presentation were 882 % for all patients, 912 % for seroACPA positive and 748 % for seroACPA negative patients (p<0.001, adjusted for age and sex) ( Table 1).

Pattern and symmetry of joint involvement at the initial presentation
At the initial presentation, wrists were the most commonly affected joints, with 43.56 % of patients having a swollen left wrist and 43.65 % a swollen right wrist. Any joint from the right MCP's was swollen in 9.56 to 34.9 % of patients and in 9.7 to 28.78 % of patients from the left MCP's. The corresponding proportions were 9.56 to 31.57 % for the right PIP's and 8.23 to 25.45 % for the left PIP's and 10.34 to 28.02 % for the right and 11.0 to 27.67 % for the left MTPs. Knees were the most commonly swollen large joints (20.86 % for right and 17.21 % for the left). The corresponding proportions were 9.6 % and 78.90 % for shoulders, 13.52 % and 123.80 % for ankles, 6.87% and 5.98 % for elbows and 1.9 % and 2.23 % for the hips (S1 Table 3).
At the initial presentation of RA, a total of 75 % of all patients had symmetrical swelling in any of the anatomical sites. In different anatomical sites, 35 % had symmetrical swelling in MCPs, 33 % in the PIPs, 34 % in wrists, 35 % in the MTPs, 12 % in the knees, 8 % in the ankles and 4 % in the elbows.
A total of 710 % of seroACPA positive patients had any symmetrical swelling, and the corresponding proportion was 9187 % for seroACPA negative patients (<0.001, adjusted for age and sex). In terms different anatomical sites, seroACPA negative patients had more symmetrical swelling in all sites,   Table 2).

Discussion
Our main observation was that early RA is still mainly presented as symmetric arthritis, as three out of four patients had symmetrical swelling in any of the anatomical sites of the 1987 criteria at the initial presentation (1). Overall, the wrists were the most commonly swollen joints by a significant margin (S1 Table 3). Symmetrical swelling was detected more often overall and at all sites in ACPA negative patients. This was an expected finding since more swollen joints are required to fulfill the criteria for seronegative RA (5). SeroACPA negative patients had also higher SJC46 at the initial presentation (median 5 versus 109). Interestingly, the presence of symmetrical swelling was only slightly higher for seroACPA negative patients in the MTPs (34 % versus 396 %, p=0.09547) ( were found between solely ACPA-positive and solely RF-positive patients, though most of the findings weren't statistically significant (Table 3). In ESR, the difference was only minor between seropositive and seronegative patients (20 versus 24, p=0.172) ( Table 2). SeroACPA positive patients were more likely to fulfill the ACR/EULAR 2010 criteria (82 % versus 78) at the time of diagnosis.
Patients with seroACPA positive RA were also current smokers more often, (21 % versus 12 % current smokers) (Table 1), as smoking is a known risk-factor for ACPA ACPA-positive RA (24). In terms of medication, GC's and MTX as monotherapy was used more frequently in patients that were diagnosed with seronegative RA. The more prevalent use of GCs, which indicates that some of the diagnosesm might have been actually polymyalgia rheumaticas, as our previous studies have suggested (10,11).
Comparison to other studies. where the median diagnostic delayduration of symptoms was five months for ACPA seropositive and four months for ACPA seronegative RA ( Table 1).
The effect of diagnostic delayduration of symptoms on the initial presentation. The overall median SJC46 was the same in all groups by diagnostic delayduration of symptoms (median 6 joints) (S2 Table 2) and median DAS28 was higher in the group of patients with a delay of < 3 months compared to patients with a delay of >6 months (4.1 versus 3.8, p=0.0168, adjusted for age and sex).
Interestingly, patients with a delay of <3 and 3-6 months were also older than in the group with a delay of >6 months, though not statistically significantly (mean age of 61 and 58 in groups with a delay of <3 and 3-6 months and 56 in the group with a delay of >6 months, p<0.001=0.581) (S2 Table   4). It has been shown that older patients utilize health care services more frequently, which might explain the finding (27). The overall median CRP and ESR were higher in patients who were  Table 4), which indicates that patients experiencing more severe symptoms and limitations in physical activity might seek health care services earlier. ACPA-positivity isn't necessarily associated with the severity of symptoms. A previous Polish study has shown that the second most important factor for the diagnostic delayduration of symptoms of RA is patients' conviction that the condition will resolve on its own (28).

Strengths and limitations
Formatted: Font: 18 pt The main strength of this study was its large patient population from almost all health care regions, in Finland and that patient data was documented recently allowing an accurate presentation of the current clinical picture.
Weaknesses. Although all health care regions are included in the quality register, at the time that was defined as the focus period, not all regions actively recorded clinical data. Therefore, probably not all patients with incident RA could be included. Furthermore, although not recommended, patients may still be diagnosed along with receiving treatment initiation in private practice, which are not involved in the quality register, yet.
One of the weaknesses in register studies is missing data, although the completeness was as high as ≥95% for joint counts and ≥78 % for PROs.

Conclusions
Our results indicate that the initial presentation of early RA is still mostly symmetric seroACPA positive arthritis. Furthermore, we found that seroACPA negative RA has significantly higher inflammatory activity and disease burden at the initial presentation by several clinical variables, compared to seroACPA positive cases. However, 25 % of patients in the current study didn't have symmetrical swelling at the initial presentation, which is why all patients with clinical joint inflammation of unknown reason ought to be tested for ACPA and RF and referred to a rheumatology unit if ACPA and/or RF isACPA they are positive. Our observations are encouraging in terms that patients experiencing more severe pain and decrease in functional ability might seek health care services earlier. We also found that ACPA-ACPA-positivity is not necessarily associated with the severity of symptoms. Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.
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